Abstract: Venous thromboembolic disease, mainly referring to deep vein thrombosis and pulmonary artery embolism, is an important perioperative complication that seriously affects the outcome of surgery. There have been many controversies about the diagnosis and treatment of perioperative venous thromboembolic disease, including the diagnostic value and rational application of D-dimer and color ultrasound; the selection, timing and duration of anticoagulant drugs; and the indications for filter implantation and thrombolytic therapy. More evidence-based data continue to revise previous diagnostic and treatment strategies and update clinicians’ views on diagnosis and treatment. The American College of Chest Physicians (ACCP) guidelines have played a pivotal role in guiding the management of perioperative thromboembolic disease. Perioperative venous thromboembolic disease refers to deep vein thrombosis (DVT) and pulmonary artery embolism (PE), which are collectively referred to as venous thromboembolism (VTE). The incidence of VTE is high and the risk is high. Currently, the annual incidence of VTE in the United States is at least 0.1% in adults and 0.5% in people aged 80 years, with >2 million new cases of VTE each year; it is estimated that 20,000 people die of PE in the United States each year, 11% of whom die within 1 h after the onset of the disease [1]. Although there is no exact epidemiological report on the incidence of perioperative VTE in China, the respective reports from different disciplines in recent years show that its incidence is increasing year by year [2-3]. The incidence of VTE is significantly higher in the perioperative period due to the superposition of these three factors: hypercoagulation, stagnant blood flow, and venous wall injury, which are the three elements of venous thrombosis. The peak time of perioperative VTE is within 1 week after surgery. 1.1 Diagnostic value of D-dimer D-dimer is the most important laboratory indicator in the diagnosis of VTE, and its value is mainly reflected in the exclusion of VTE when its level is not elevated, as it is a specific plasma protein formed by fibrinolytic enzymes that lyse cross-linked fibrin. D-dimer levels are elevated in acute VTE events, making D-dimer a sensitive screening indicator for recent DVT or PE. Other conditions including bacteraemia, pregnancy, surgery, and cachexia can also lead to elevated D-dimer levels, making D-dimer a highly sensitive but not very specific indicator for the diagnosis of VTE. All patients suspected of DVT should be tested for D-dimer, and two commonly used assays include: latex agglutination and ELISA, while the ELISA method measures results with higher specificity. 95% of the negative predictive value of D-dimer <0.5 mg/L (ELISA method) [4]. 1.2 Diagnosis of DVT The diagnosis of DVT relies mainly on ultrasonography. Compression ultrasound (CUS) is a widely used noninvasive test to diagnose patients with suspected DVT. It has a sensitivity of 97% and a specificity of 98% for the diagnosis of proximal DVT. However, CUS only examines the veins in the groin and N fossa, and is less sensitive and specific for the diagnosis of distal DVT in the lower extremities. Complete compression ultrasound (CCUS) detects continuous femoral, N and calf veins by compression ultrasound (2 cm/stage), and the accuracy of CCUS in diagnosing distal DVT is significantly improved [5]. Deep venography of the lower extremities was once the gold standard for the diagnosis of DVT, but it was gradually replaced by ultrasonography because of its disadvantages such as invasiveness and X-ray radiation. 1.3 Diagnosis of PE The diagnosis of PE mainly relies on multilayer spiral CT, pulmonary arteriography is the gold standard for the diagnosis of PE, but it is less used due to its invasive nature, and ventilation and perfusion scanning is still an important examination method. Multilayer spiral CT is a new diagnostic tool for PE with the advantages of rapid, non-invasive and accurate. Its short imaging time, thin layer scanning, extensive coverage and good image post-processing quality have significantly improved the diagnosis of pulmonary embolism. Multilayer spiral CT angiography can clearly show the segmental pulmonary arteries and most subsegmental pulmonary arteries, and its subsegmental PE display rate reaches 94%, among which the display rates of grade 5 and 6 branches are 74% and 35%, respectively. Pulmonary angiography is the gold standard for the diagnosis of PE, with few false positives and less likely to be missed; however, its use in clinical practice is decreasing because it is an invasive test, more expensive and has more complications. At present, it is mainly used for those who have a high clinical suspicion of PE and the diagnosis cannot be confirmed by noninvasive tests, or in the context of pulmonary artery mechanical thrombolysis. Ventilation-perfusion lung scan has been the preferred noninvasive diagnostic method for pulmonary embolism in the past, with high specificity and sensitivity, but it is less intuitive than spiral CT in showing the specific embolic site and morphology, and the two complement each other to further improve the diagnostic rate [6]. 1.4 Diagnostic strategy for VTE The 9th edition of the American College of Chest Physicians (ACCP) guidelines recommend the best strategy for diagnosis: (1) For patients with a suspected first lower extremity DVT, it is recommended that a clinical assessment of the pretest probability of DVT (Well's scoring system) should guide the diagnostic process, rather than performing the same test in all patients (level 2B). (2) For patients with low pre-test probability of first lower extremity DVT, D-dimer level testing or proximal CUS is recommended over no diagnostic testing (level 1B), angiography (level 1B), and CCUS (level 2B). (3) For patients with moderate pretest probability of first DVT, highly sensitive D-dimer level testing, proximal CUS or CCUS (level 1B) is recommended. (4) For patients with a high pre-test probability of first DVT, CUS or CCUS (level 1B) is recommended [7]. The diagnosis of first DVT is favored by the combination of pre-test probability assessment, D-dimer testing, and ultrasonography. 2 Prevention of perioperative VTE 2.1 Preventive means of VTE An important part of the treatment of perioperative VTE is prevention, which is more practical than any treatment. prevention of VTE mainly includes the application of mechanical antithrombotic devices and anticoagulant drugs. 2.1.1 Mechanical antithrombotic devices, including compression elastic stockings, intermittent inflatable compression devices, and plantar venous pumps, can increase venous blood return to the lower extremities and reduce venous blood pooling, thus preventing the occurrence of perioperative VTE. The advantages of mechanical anticoagulation devices are that they prevent thrombosis without increasing the risk of bleeding; the disadvantages are that they are not suitable for people with lower extremity trauma and lower extremity surgery, low patient compliance, and limited clinical application. 2.1.2 Anticoagulant drugs Anticoagulant drugs are divided into two categories according to the mode of administration: parenteral drugs and enteral drugs. Parenteral drugs include common heparin, low molecular heparin, anti-factor xa (sulforaphane sodium) and prothrombin (factor IIa) inhibitors (argatroban). Heparin mainly binds by ATIII and thus acts as an anticoagulant, with the advantages of rapid onset of action and ease of monitoring and counteracting, and the disadvantage of significantly increased risk of bleeding after heparin application. Low-molecular heparin acts mainly by inhibiting factor Xa, while inhibiting factor IIa is weaker, so the risk of bleeding is significantly reduced. The common disadvantage of regular heparin and low molecular heparin is that they cause heparin induced thrombocytopenia (HIT). Fondaparinux sodium is the world's first indirect inhibitor of the Xa factor, with the advantage of rapid onset of action, long-lasting effect (once daily) and no HIT. Argatroban is a thrombin inhibitor that reversibly binds to the active site of thrombin to exert its anticoagulant effect. Enterally administered anticoagulants include the classic vitamin K antagonist (VKA) warfarin, which inhibits blood clotting by interfering with hepatic synthesis of vitamin K-dependent coagulation factors II, VIII, IX, and X. The disadvantage of warfarin is that it has a narrow therapeutic window and tends to cause major bleeding. Newer enterally administered anticoagulants are direct factor Xa inhibitors such as rivaroxaban and thrombin inhibitors such as dabigatran. Rivaroxaban does not require coagulation monitoring and dose adjustment during administration and has similar anticoagulant effects to warfarin but with a significantly reduced risk of bleeding. Dabigatran directly inhibits free and thrombin-bound thrombin, thereby blocking the catalytic formation of fibrinogen into fibrin, and its efficacy against VTE is not inferior to that of enoxaparin [8]. 2.2 Prevention strategies for VTE The 9th edition of the ACCP guidelines makes the following recommendations for VTE prevention in non-orthopedic surgery: (1) When the risk of VTE is low (incidence <0.5%; refer to Rogers or Caprini scoring system), no specific pharmacological (class 1B) or mechanical (class 2C) antithrombotic prophylaxis is recommended, except for early bed activity. (2) When the risk of VTE is low (0.5% to 1.5% incidence), mechanical anticoagulation prophylaxis (preferring an intermittent insufflatable compression device) is recommended (class 2C). (3) When the risk of VTE is moderate (incidence of 1.5% to 3.0%) and there is no risk of major bleeding, low molecular weight heparin (class 2B), low dose normal heparin (class 2B) or intermittent insufflatable compression devices (class 2C) are recommended. (4) When the risk of VTE is high (3%-6%) and there is no risk of major bleeding, pharmacological anticoagulation prophylaxis, such as low molecular weight heparin (class 1B) or low dose plain heparin (class 1B), combined with mechanical anticoagulation prophylaxis (class 2C), is recommended. (5) For patients at higher risk of VTE and who will undergo abdominal or pelvic tumor surgery, extended postoperative anticoagulation prophylaxis with low-molecular-quality heparin (up to 4 weeks postoperatively) is recommended (level 1B). (6) For patients at moderate to high risk of VTE with risk of major bleeding or extremely severe bleeding consequences, mechanical antithrombotic prophylaxis (preferring intermittent insufflatable compression devices) is recommended; pharmacologic anticoagulation prophylaxis should be initiated only when the risk of bleeding is reduced to a low level (Class 2C). (7) For patients at either risk level, the administration of an inferior vena cava filter is not recommended as primary prophylaxis (level 2C) [9]. 3 Treatment of perioperative VTE The treatment of VTE consists mainly of anticoagulation and thrombolytic therapy, and filter implantation is limited to some patients with indications for surgery. Some other treatments include mechanical thrombolysis, embolization and thrombectomy, which can further improve the treatment outcome when applied to appropriate patients. 3.1 Anticoagulation for VTE Anticoagulation is the cornerstone of VTE treatment and should be given to all patients who are not contraindicated to treatment. In China, the current protocol is to give parenteral anticoagulants, such as low-molecular heparin or sodium sulfadepril, early after the diagnosis of VTE, and then gradually transition to enterally administered anticoagulants, commonly used is warfarin. Rivaroxaban can be used as a long-term oral anticoagulant for those who have contraindications to warfarin use. The 9th edition of ACCP guidelines makes recommendations on the anticoagulation intensity, choice of anticoagulant and duration of treatment for patients with VTE in different conditions: (1) For patients with acute DVT or PE, parenteral anticoagulants (class 1B) or rivaroxaban are recommended as initial anticoagulation therapy; low-molecular-weight heparin or sulfadoxine sodium is recommended over intravenous (class 2C) or subcutaneous (class 2B) plain heparin therapy, and Early oral VKA therapy (e.g., on the day of parenteral anticoagulation application) and continuation of parenteral anticoagulation for at least 5 d until INR is 2.0 or higher for at least 24 h. (2) For patients with proximal DVT or PE, the recommended duration of anticoagulation therapy is 3 months (class 1B). (3) For patients with first proximal DVT or PE caused by surgical or transient non-surgical risk factors, the recommended duration of anticoagulation therapy is 3 months (level 1B; the recommended level is reduced to level 2B when caused by non-surgical risk factors and the risk of bleeding is low or moderate). (4) For patients with unprovoked first proximal DVT or PE with low or moderate risk of bleeding, long-term anticoagulation is recommended (level 2B); for patients with high risk of bleeding, continuous anticoagulation for 3 months is recommended (level 1B). (5) For patients with a first proximal DVT or PE in combination with cancer, long-term anticoagulation is recommended (level 1B; if accompanied by a high risk of bleeding, the recommended level is reduced to level 2B). Low-molecular-weight heparin therapy is recommended (Grade 2B). If low-molecular heparin is not available, VKA is preferable to dabigatran or rivaroxaban (grade 2B). (6) In patients with extensive superficial vein thrombosis, prophylactic doses of sodium fondaparinux or low-molecular-weight heparin (grade 2B) are recommended, with fondaparinux being superior to low-molecular-weight heparin (grade 2C) [10]. 3.2 Thrombolysis for VTE Another important treatment component of VTE is thrombolysis, which aims to reduce the thrombotic load, restore the patency of the venous lumen, and reduce the incidence of post thrombotic syndrome (PTS). Thrombolysis can be performed by systemic systemic thrombolysis or by direct local thrombolysis via catheter. Although the former can promote venous thrombosis and protect the venous valves in patients with acute DVT, the risk of bleeding complications is significantly higher than that of anticoagulation alone. Direct thrombolysis via catheter allows the thrombolytic drug to directly contact the thrombus, with high local drug concentration and better thrombolytic effect; while the drug concentration in other parts of the body is low and the risk of bleeding is significantly reduced, which has become a more preferred treatment by clinicians. The commonly used thrombolytic drugs are urokinase, recombinant streptokinase and tissue-type fibrinogen activator. However, the 9th edition of ACCP guidelines still recommends anticoagulation over direct transcatheter thrombolysis for routine DVT or PE (Class 2C). More scholars, including the author, believe that transcatheter thrombolysis is reasonable if the patient has a high probability of PTS and the risk of bleeding from local thrombolysis is not significant [11]. The 9th edition of ACCP guidelines states that systemic thrombolysis is reasonable when PE patients have hypotension [systolic blood pressure <90 mmHg (1 mmHg=0.133 kPa) or a sudden decrease of 40 mmHg for >15 min] and the risk of bleeding is not high (level 1B); systemic thrombolysis by drug infusion within a short period of time (2 h) is recommended. For patients with PE in whom systemic thrombolysis is ineffective, the guidelines suggest that direct thrombolysis via catheter may be performed (grade 2C) [10]. 3.3 Inferior vena cava filter implantation Inferior vena cava filter implantation can effectively prevent PE, but the filter itself is a foreign body that can aggravate thrombosis, and there are complications such as displacement and punctured vessels after implantation. In recent years, the use of temporary filters has reduced the number of long-term complications after implantation. Retrievable filters can be implanted as permanent filters or removed after a period of high risk of thrombosis, making their application more flexible. Previously, there has been a tendency to overuse inferior vena cava filters, both domestically and abroad. The current 9th edition of the ACCP guidelines only recommend filter implantation in VTE patients with contraindications to anticoagulation, and recommend the use of temporary filters that can be removed for anticoagulation when the risk of bleeding has ceased. There is an increased risk of recurrence of thrombosis after filter implantation, and we have previously recommended prolonged anticoagulation in patients after filter implantation, but ACCP recommends maintaining the duration of routine anticoagulation in patients with filter implantation [10]. 3.4 Other treatments include thrombectomy and mechanical thrombolysis. Thrombectomy is currently less commonly used in patients with either DVT or PE because of its greater invasiveness and higher risk of postoperative recurrent thrombosis. Mechanical thrombolysis can further reduce thrombolytic drugs, reduce the risk of bleeding and improve the effectiveness of thrombolysis by combining thrombolytic drugs with vibration to accelerate thrombus dissolution. The 9th edition of the ACCP guidelines does not recommend routine thrombectomy in patients (class 2C), and mechanical thrombolysis has not been evaluated. For hypotensive PE patients in whom systemic thrombolysis is ineffective, the guidelines recommend that thrombectomy may be performed (class 2C) [10]. 4 The status and changing role of aspirin in anticoagulation Aspirin is an ancient drug with a history of more than 100 years that mainly acts as an antiplatelet coagulant. Previously, we believed that aspirin was effective in preventing arterial thrombosis and ineffective in preventing venous thrombosis. In recent years, the role and positioning of aspirin in anticoagulation has caused a renewed discussion. In the ACCP and American Academy of Orthopaedic Surgeons (AAOS) guidelines prior to 2012, the views on the role of aspirin in anticoagulation were different. The 8th edition of the ACCP guidelines, in which the goal of perioperative anticoagulation is to prevent any VTE without concern for bleeding risk, argues against the use of aspirin for any anticoagulation purpose and strongly recommends low-molecular heparin for anticoagulation, whereas the AAOS guidelines also focus on the bleeding complications of anticoagulation and therefore include a variety of drugs, including aspirin, as options in the AAOS guidelines . The 9th edition ACCP guidelines take into account the risk of bleeding, and the purpose of perioperative anticoagulation is to prevent symptomatic VTE rather than all VTE; and one of the largest studies on the anticoagulant effect of aspirin during this period showed that the anticoagulant effect of 28 d of oral aspirin in total hip replacement was not inferior to that of dalteparin sodium [12]. Therefore, the 9th edition of the ACCP guidelines recommends that aspirin can be used alone as an anticoagulant in orthopaedic surgery (Class 1B). Although the guidelines do not directly mention whether aspirin can be used as a stand-alone anticoagulant in non-orthopedic surgery, they can be used as a reference whereby aspirin is also an option as a perioperative anticoagulant for those patients for whom the use of low-molecular heparin is contraindicated [7].